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Effect of a COVID-19-Heterologous Vaccination Schedule on Haemostasis: A Subanalysis of the Phase 2, Multicentre, Randomised, Controlled CombiVacS Study

27 Pages Posted: 1 Mar 2022

See all articles by Nora V. Butta

Nora V. Butta

Hospital Universitario La Paz

Elena G. Arias-Salgado

Hospital Universitario La Paz

Elena Monzón Manzano

Hospital Universitario La Paz

Paula Acuña

Hospital Universitario La Paz

Maria T. Álvarez Román

Hospital Universitario La Paz

Antonio Buño-Soto

Hospital Universitario La Paz - Department of Laboratory Medicine

Juan C. Ramos-Ramos

Hospital Universitario La Paz

Cristóbal Belda-Iniesta

Carlos III Institute of Health

Jesús Frías

La Paz University Hospital - Servicio de Farmacología Clínica

Antonio J Carcas

La Paz University Hospital - Servicio de Farmacología Clínica

Lucía Martínez de Soto

Hospital Universitario La Paz

R de Miguel Buckley

Hospital Universitario La Paz

David Lora

Instituto de Investigación Sanitaria Hospital "12 de Octubre" - Hospital Universitario 12 de Octubre

María Teresa García-Morales

Instituto de Investigación Sanitaria Hospital "12 de Octubre" - Hospital Universitario 12 de Octubre

Alberto M Borobia

La Paz University Hospital - Servicio de Farmacología Clínica

JR Arribas

Universidad Autónoma de Madrid - Hospital Universitario La Paz. IdiPAZ

Víctor Jiménez Yuste

Hospital Universitario La Paz

More...

Abstract

Background: Several cases of unusual thrombotic events and thrombocytopenia have occurred after vaccination with recombinant adenoviral vectors encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to elucidate the impact of a COVID-19 heterologous vaccination schedule including priming with an adenovirus vaccine on haemostasis and coagulation profile.

Methods: Adult participants were vaccinated with a single dose of ChAdOx1-S. Between 8–12 weeks after vaccination they were randomly assigned (2:1) to receive either BNT162b2 vaccine (intervention group) or continue observation (control group).Samples drawn before and 28 days after a vaccination with BNT162b2 were analyzed for platelet count and markers of haemostasis (D-dimer, Anti-heparin PF4 antibodies, cell-free DNA, plasminogen activator inhibitor-1, thrombin generation, and serum capacity to activate platelets).

Findings: Platelet count from all participants after receiving BNT162b2 was within normal range.Anti-PF4 antibodies were present in 26% and 18% of subjects from the control and intervention group, respectively, at day 28. In most cases levels of anti-PF4 antibodies were high before receiving BNT162b2. Moreover, serum from these participants did not affect activity state of platelets from healthy controls. There were no differences between groups in PAI-1 and cfDNA plasma levels. According to D-dimer plasma concentration, thrombin generation test showed that none of the participants had a procoagulant profile.

Interpretation: Our data support the safety in terms of alteration of haemostasis and coagulation of the heterologous vaccination against COVID-19 infection with ChAdOx1-S and a second dose with BNT162b2.Funding Instituto de Salud Carlos III.

Trial Registration Details: This study is registered with EudraCT (No. 2021-001978-37) and ClinicalTrials.gov (NCT04860739)

Funding Information: This work is funded by the Instituto de Salud Carlos III, a Spanish public body assigned to the Ministry of Science and Innovation that manages and promotes public clinical research related to public health. The Spanish Clinical Trials Platform is a public network funded by the Instituto de Salud Carlos III (grant numbers PTC20/00018 and PT17/0017), the State Plan for Research, Development, and Innovation 2013–16, the State Plan for Scientific and Technical Research and Innovation 2017–20, and the Subdirectorate General for Evaluation and Promotion of Research, Instituto de Salud Carlos III, cofinanced with FEDER funds. CombiVacS was designed under the umbrella of the VACCELERATE project. VACCELERATE received funding from the EU's Horizon 2020 Research and Innovation Programme (grant agreement numbers 101037867 and 860003). The Instituto de Salud Carlos III is the Spanish partner in the VACCELERATE project. The authors thank all trial participants. The authors thank Esther Prieto for editorial assistance and writing support (employed by Hospital Universitario La Paz; funded by the Instituto de Salud Carlos III, grant number PCT20/00018).

Declaration of Interests: CB-I is the deputy general manager of the Instituto de Salud Carlos III. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work. AMB has received fees from Janssen and Pfizer, outside of the submitted work. VJY and MTAR are principal investigators of clinical trials sponsored by Pfizer, NovoNordisk, Roche, Sanofi, SOBI, Takeda, and Grifols outside of the submitted work. RdMB reports personal fees (speaker fee) and non-financial support from ViiV and Gilead. All other authors declare no competing interests.

Ethics Approval Statement: The trial complies with the principles of the Declaration of Helsinki and Good Clinical Practice, and was approved by the Spanish Agency of Medicines and Healthcare Products and by the ethics committee at La Paz University Hospital. All participants provided written informed consent before enrolment.

Keywords: COVID-1, heterologous vaccination, haemostasis

Suggested Citation

Butta, Nora V. and Arias-Salgado, Elena G. and Monzón Manzano, Elena and Acuña, Paula and Álvarez Román, Maria T. and Buño-Soto, Antonio and Ramos-Ramos, Juan C. and Belda-Iniesta, Cristóbal and Frías, Jesús and Carcas, Antonio J and Martínez de Soto, Lucía and de Miguel Buckley, R and Lora, David and García-Morales, María Teresa and Borobia, Alberto M and Arribas, JR and Jiménez Yuste, Víctor, Effect of a COVID-19-Heterologous Vaccination Schedule on Haemostasis: A Subanalysis of the Phase 2, Multicentre, Randomised, Controlled CombiVacS Study. Available at SSRN: https://ssrn.com/abstract=4046663 or http://dx.doi.org/10.2139/ssrn.4046663

Nora V. Butta

Hospital Universitario La Paz ( email )

Madrid
Spain

Elena G. Arias-Salgado

Hospital Universitario La Paz ( email )

Madrid
Spain

Elena Monzón Manzano

Hospital Universitario La Paz ( email )

Madrid
Spain

Paula Acuña

Hospital Universitario La Paz ( email )

Madrid
Spain

Maria T. Álvarez Román

Hospital Universitario La Paz ( email )

Madrid
Spain

Antonio Buño-Soto

Hospital Universitario La Paz - Department of Laboratory Medicine ( email )

Madrid
Spain

Juan C. Ramos-Ramos

Hospital Universitario La Paz ( email )

Madrid
Spain

Cristóbal Belda-Iniesta

Carlos III Institute of Health ( email )

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Jesús Frías

La Paz University Hospital - Servicio de Farmacología Clínica ( email )

Madrid
Spain

Antonio J Carcas

La Paz University Hospital - Servicio de Farmacología Clínica ( email )

Madrid
Spain

Lucía Martínez de Soto

Hospital Universitario La Paz ( email )

Madrid
Spain

R De Miguel Buckley

Hospital Universitario La Paz ( email )

David Lora

Instituto de Investigación Sanitaria Hospital "12 de Octubre" - Hospital Universitario 12 de Octubre ( email )

Madrid
Spain

María Teresa García-Morales

Instituto de Investigación Sanitaria Hospital "12 de Octubre" - Hospital Universitario 12 de Octubre ( email )

Madrid
Spain

Alberto M Borobia (Contact Author)

La Paz University Hospital - Servicio de Farmacología Clínica ( email )

Madrid
Spain

JR Arribas

Universidad Autónoma de Madrid - Hospital Universitario La Paz. IdiPAZ ( email )

Campus Cantoblanco
C/Kelsen, 1
Madrid, Madrid 28049
Spain

Víctor Jiménez Yuste

Hospital Universitario La Paz ( email )

Madrid
Spain

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